Atomising nozzle

ABSTRACT

An atomising nozzle assembly and a method for generating a respirable spray of droplets of a size suitable for medical inhalation therapy from a liquid medicament. The nozzle assembly comprises a gas nozzle (2) for producing a jet of gas and a liquid nozzle (3) for ejecting the liquid to be atomised into the jet of gas at a position downstream of the gas nozzle (2). The gas nozzle (2) and the liquid nozzle (3) are configured such that the jet of gas impinges on the liquid at an acute angle to atomise the liquid. The nozzle assembly and method can create a respirable spray using a gas/liquid mass ratio of less than 0.5.

This application Ser. No. 09/043,679 is the National Stage ofPCT/EP96/04153.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to atomising nozzles used for hand held sprayerssuch as so-called aerosols and pump type atomisers, intended for theapplication of liquid pharmaceutical products.

2. Description of the Related Art

Aerosol type sprayers are used throughout the world for dispensing awide range of products, for example, hair lacquer, furniture polish,cleaners, paint, insect killers and medicaments. Until recently,chlorofluorocarbons (CFC's) were the most common of the propellant gasesused in aerosols because they are inert, miscible with a wide range ofproducts, are easily liquefied under low pressures, give a substantiallyconstant product flow-rate, and can produce sprays of droplets havingmean diameters in the range of 3 to over 100 micrometers. However, inthe 1970's it was confirmed that CFC's were probably responsible fordepleting the Earth's protective ozone layer, and in 1987, mostcountries signed the Montreal Protocol to phase out the use of CFC's andhave since agreed to stop use of CFC's for non-essential applications bythe end of 1995. One notable exemption to this deadline for cessation ofuse is in relation to metered dose inhalers (MDI's) for medicaments,which are regarded as an essential use of CFC's, but even this use ofCFC's will eventually be phased out.

Gases such as air and nitrogen have the advantages of causing noenvironmental damage, being non-flammable and causing no ill effects ifinhaled. Such gases can be used to propel liquid from a canister, butwith a simple orifice or a swirl orifice very high pressures arerequired to produce a fine spray suitable for an MDI.

Other types of aerosol generators for delivery of liquid pharmaceuticalproducts exist for research and hospital applications, such asnebulisers. However, these generally contain baffles to remove largerdroplets and use high air flowrates so making them unsuitable for use inportable, convenient atomisers.

It is also possible to force liquid at high pressure through a verysmall hole (5-10 micrometers diameter) to produce droplets of about 5micrometers diameter, but these methods are unsuitable or uneconomic forlarge scale manufacture, mainly because of the difficulty in making verysmall holes in a suitable material, and, to prevent blockage of thehole, the need for exceptional cleanliness in the manufacture of theparts, together with ultrafiltration of the fluid to be sprayed.

Many of the drugs used in the treatment of respiratory disorders areinsoluble in vehicles such as water and are dispensed as suspensions.The drug particles are produced in a respirable size of 1-5 micrometers.Particles of this size tend to block the very small holes (5-10micrometers) used by known devices.

For veterinary and some human vaccination applications, high pressure(125-500 bars) spring or gas operated pumps (so-called needle-lessinjectors) are in common use to inject a jet of drug through the skin("intra-dermal injection") without the use of needles, and attachmentsare available to convert the jet to a spray for administering drugs tothe nasal passages of large animals such as swine. However, the smallestdroplet size obtainable is in the order of 40 micrometers, and the rangeof applications for these injectors is limited.

Compressed air atomisers such as air brushes and commercial paintsprayers consume large quantities of air, and to obtain droplets of 5micrometers with water for example, a gas to liquid mass ratio of over36:1 is required which is impractical for convenient, portable sprayers.

Spray nozzles in which a liquid is atomised by impingement of multiplejets of fluid on each other, e.g. air and liquid jets, are known. U.S.Pat. No. 5,385,304 describes an air assisted atomising spray nozzle inwhich a jet of liquid is atomised within a mixing chamber by theshearing action of several jets of air directed in substantiallyperpendicular relation to the liquid jet. The nozzle may be used todeliver liquid in a finely atomised state and suitable applicationsinclude use for the delivery of agricultural chemicals and pesticides,humidifying systems and scrubbing systems for coal furnaces. The nozzledescribed is believed to provide a high air efficiency by the use of anopposing cross-flow of air and the air/liquid mass ratio of theembodiment described is from 0.13 to 0.27. Although the spray particlesize is not defined, the nozzle is described as producing a fine liquiddroplet spray, and the applications discussed suggest that it mightproduce droplet sizes down to a minimum of 50 micrometers in diameter.

For MDI's used for treating certain respiratory disorders it isessential that the aerodynamic particle size should be less than 15micrometers, preferably less than 10 micrometers, so that the dropletsare able to penetrate and deposit in the tracheobronchial and alveolarregions of the lung. For a spray composed of droplets with a range ofsizes, more than 5% by weight of the droplets should have an aerodynamicdiameter less than 6.4 micrometers, preferably more than 20% by weightof the particles have an aerodynamic diameter less than 6.4 micrometers.

Inhalers may also be designed to deliver drugs to the alveolar sacs ofthe lung to provide a route for adsorption into the blood stream ofdrugs that are poorly adsorbed from the alimentary tract. To reach thealveoli it is essential that the aerodynamic diameter of the particlesis less than 10 micrometers, preferably 0.5-5 micrometers

Current thinking suggests that to create smaller spray droplets fromimpinging fluid nozzles it is necessary to increase the gas/liquid massratio (GLR) resulting in an associated increase in gas reservoir sizerequired to deliver the necessary mass of propellant. However, for theapplication of such technology to portable hand held inhalation devices,it is desirable for the GLR to be small to limit the size of reservoirrequired. The alternative of using hand or finger driven, or primedpumps to meter and produce the liquid and gas flows also requires thatthe volume and pressure of gas required are minimised to allow a smallpump size and to minimise the effort required by the patient.

SUMMARY OF THE INVENTION

The present invention aims to provide a design of atomising nozzleassembly suitable for use in a hand held inhalation device and which iscapable of being used to produce a spray of droplets of a size suitablefor inhalation, without the use of conventional liquefied gaspropellants.

According to the present invention there is provided an atomising nozzleassembly for generating a respirable spray of droplets of a sizesuitable for medical inhalation therapy from a liquid medicament, thenozzle assembly comprising a gas nozzle for producing a jet of gas and aliquid nozzle for ejecting the liquid to be atomised into the jet of gasat a position downstream of the gas nozzle, wherein the gas nozzle andthe liquid nozzle are configured such that the jet of gas impinges onthe liquid at an acute angle to atomise the liquid.

The present invention further provides an atomising nozzle assemblycomprising at least one nozzle for ejecting the liquid to be atomisedand at least one nozzle for producing a jet of gas, the at least oneliquid nozzle and the at least one gas nozzle being configured such thatthe liquid is impacted upon by the gas jet so as to produce a respirablespray of droplets of a size suitable for medical inhalation therapy, thegas to liquid mass flowrate ratio being less than 0.5.

By use of a gas and liquid nozzle configuration wherein the jet of gasimpinges on the liquid at an acute angle it is possible to create arespirable spray with a GLR less than 0.5.

Preferably the gas to liquid mass ratio is 0.2 or less.

Suitably, the gas nozzle is at least partially obscured by the liquidnozzle such that the liquid is delivered from the liquid nozzle directlyinto the jet of gas.

Preferably the liquid nozzle is bevelled.

Suitably, the liquid and gas nozzles have an outlet diameter between 50micrometers and 200 micrometers.

The liquid and gas nozzles are suitably configured to give a fluidimpingement angle of between 30° and 90°. Preferably the liquid and gasnozzles are configured to give a fluid impingement angle of between 40°and 60°.

Suitably, the liquid nozzle outlet is positioned up to 10 gas nozzleoutlet diameters downstream of the gas nozzle outlet. Preferably theliquid nozzle outlet is positioned between 1 and 4 gas nozzle outletdiameters downstream of the gas nozzle outlet.

In a further aspect of the present invention there is provided a methodfor generating a respirable spray of droplets of a size suitable formedical inhalation therapy from a liquid medicament by introducing thesaid liquid into a jet of gas, wherein the jet of gas impinges on theliquid at an acute angle to the direction of flow of the liquid.

The present invention also provides a method for creating a respirablespray of droplets of a size suitable for medical inhalation therapy froma liquid medicament by introducing the said liquid into a jet of gassuch that the said liquid is impacted upon by the said jet of gas, thegas to liquid mass flowrate ratio being less than 0.5.

Preferably the gas to liquid mass flowrate ratio is 0.2 or less.

In a preferred embodiment the shapes and sizes of the liquid and gassupply nozzles are chosen to maximise the inhalable proportion of thespray whilst minimising the amount of gaseous propellant required. Thisrequires that the liquid ejection nozzle has a shape and position thatdisturbs the gas jet in such a manner that the break-up of the liquidoccurs throughout the cross section of the gas flow and, in particular,in regions of high gas velocity, and that turbulence, vortex formationand shock wave production created by interaction of the gas jet with theliquid nozzle act to improve break-up into small droplets and thedispersion of droplets across the gas jet.

The invention will now be described with reference to the accompanyingdrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1a, 1b, 1c and 1d are section, end and schematic views showing aliquid and gas nozzle configuration according to the invention;

FIGS. 2a, 2b, 2c and 2d are graphs showing the percentage by mass ofdrops less than 6.4 micrometers in diameter created with varyingparameters relating to the liquid and gas nozzles as shown in FIGS. 1a,1b and 1c;

FIGS. 3a, 3b and 3c are perspective and sectional views showingalternative shapes and arrangements of liquid and gas nozzleconfigurations according to the invention;

FIG. 4 is a graph showing average drop sizes produced by a nozzleaccording to the invention with varying liquid flowrates; and

FIG. 5 is a graph showing mean drop velocities produced by a nozzleaccording to the invention.

DETAILED DESCRIPTION OF THE INVENTION

Referring to FIGS. 1a, 1b, 1c and 1d, a preferred form of the atomisingnozzle assembly 1 consists of a cylindrical gas nozzle 2 having acircular orifice of 125 microns internal diameter, and a bevelled liquidnozzle 3 of a similar internal diameter but presenting an elipticaloutlet orifice positioned partly in front of gas nozzle 2. Liquid nozzle3 is arranged such that the liquid outlet orifice is positionedapproximately 1 gas outlet orifice diameter downstream of the gas outletorifice. The lateral position of liquid nozzle 3 relative to gas nozzle2 may be expressed as percentage obscuration of the gas nozzle and isdetermined according to FIG. 1c by the equation:

    L=100 r/D(%).

The liquid and gas nozzles may be made from stainless steel hypodermic316 or any other suitable material. Gas nozzle 2 and liquid nozzle 3define an acute angle of 40° between them.

In use, air 4 is delivered at sonic velocity through gas nozzle 2 andliquid 5 under pressure is introduced into the gas jet at a velocityaround 1.4 m/s through liquid nozzle 3. For the purposes of theexperimental results given below the liquid used is water. However, theliquid may, for example, consist of an aqueous suspension or solution ofa medicament or other bioactive molecule. Bioactive molecules suitablefor this purpose include proteins, peptides, oligonucleosides and genessuch as DNA complexed with an appropriate lipid carrier, for example,DNA encoding cystic fibrosis transmembrane conductance regulator (CFTR)protein/cationic lipid complex, useful for the treatment of cysticfibrosis.

Medicaments suitable for this purpose are, for example for the treatmentof respiratory disorders such as asthma, bronchitis, chronic obstructivepulmonary diseases and chest infections. Additional medicaments may beselected from any other suitable drug useful in inhalation therapy andwhich may be presented as an aqueous suspension or solution. Appropriatemedicaments may thus be selected from, for example, analgesics, e.g.codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginalpreparations, e.g. diltiazem; antiallergics, e.g. cromoglycate,ketotifen or neodocromil; antiinfectives e.g. cephalosporins,penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine;antihistamines, e.g. methapyrilene anti-inflammatories, e.g.fluticasone, flunisolide, budesonide, tipredane or triamcinoloneacetonide; antitussives, e.g. noscapine; bronchodilators, e.g.salmeterol, salbutamol, ephedrine, adrenaline, fenoterol, formoterol,isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterolorciprenaline, or(-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol;diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropineor oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone;xanthines e.g. aminophylline, choline theophyllinate, lysinetheophyllinate or theophylline and therapeutic proteins and peptides,e.g. insulin or glucagon. It will be clear to a person skilled in theart that, where appropriate, the medicaments may be used in the form ofsalts (e.g. as alkali metal or amine salts or as acid addition salts) oras esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) tooptimise the activity and/or stability of the medicament. Preferredmedicaments are salbutamol, salbutamol sulphate, salmeterol, salmeterolxinafoate, fluticasone propionate, beclomethasone dipropionate andterbutaline sulphate. It is to be understood that the suspension orsolution of medicament may consist purely of one or more activeingredients.

The shape and position of the liquid nozzle 3 causes interaction withthe air jet such that the liquid flows mainly to the tip 6 of the nozzleand detaches and rapidly atomises in the high velocity gas zone to forma slow moving spray. Slow moving sprays are particularly suitable fordelivery to the tracheobronchial and alveolar regions of the lung asthey reduce the amount of impingement of droplets at the back of thethroat which tends to result from faster moving sprays. Slow movingsprays are also beneficial to the user by facilitating coordination ofactuation of the device with the act of inhalation. The size of thedroplets is controlled, inter alia, by the respective gas and liquidflowrates, and the shapes of both nozzles. The positioning of liquidnozzle 3 in front of gas nozzle 2 creates turbulence, vortex sheddingand shock wave formation in the jet of air which is beneficial toatomisation of the liquid 5, and as described with reference to FIG. 2abelow, it has been found that use of a bevelled orifice rather than asquare edge orifice allows increased flexibility with respect to thelateral position of the liquid nozzle relative to the gas nozzle, sorelaxing the tolerances required during manufacture.

FIG. 1d shows how liquid and gas nozzles might be incorporated into asingle moulded component. The nozzles themselves might be manufacturedby laser drilling or by injection moulding with or without hypodermiccapillary inserts.

FIG. 2a demonstrates the results of tests carried out on one atomisingnozzle with a bevelled liquid orifice as described above and oneatomising nozzle with a square edge liquid orifice using differentliquid flowrates but constant gas flowrate to determine how the lateralposition of the liquid nozzle relative to the gas nozzle (percentageobscuration) affects the percentage of fine particle mass created; thatis droplets with a diameter less than 6.4 micrometers as measured by thedeposition of spray in the second stage of a twin impinger device. It isevident from

FIG. 2a that the optimum results at liquid flowrates of 1.0 ml/min and1.2 ml/min are obtained at approximately 50% obscuration, though thedeterioration of spray characteristics with different obscuration valuesis much less marked with the bevelled orifice than with the square edgeorifice.

FIG. 2b shows the variation in fine particle mass creation withvariation in GLR for one atomising nozzle with a bevelled liquid orificeand one atomising nozzle with a square edge liquid orifice usingdifferent percentage obscurations with constant liquid flowrate. Thisdemonstrates that a significant improvement in atomisation efficiency isobtained using the bevelled liquid orifice with over 20% fine particlemass being attained with a GLR of around 0.12.

FIG. 2c shows the variation in fine particle mass created with variationin GLR at selected liquid flowrates and gas nozzle obscurations using abevelled liquid nozzle. This figure demonstrates that improvedperformance results from increased GLR and that 20% deposition isachieveable at a GLR of around 0.12 with 50% obscuration.

FIG. 2d shows the optimum gas nozzle obscuration for different gasflowrates using a constant liquid flowrate of 1.0 ml/min. Formanufacturing purposes it is desirable to be able to achieve therequired spray characteristics over a range of liquid orifice positionsin order to allow for manufacturing inaccuracies. This also aids theachievement of consistent performance throughout the lifetime of thenozzle. From FIG. 2d it is clear that for the creation of 20% ofdroplets with a diameter less than 6.4 micrometers, gas flowrates of 120ml/min and above will allow for some tolerance on obscuration.

Increasing the liquid flowrate allows the gas flowrate to be increasedproportionately to maintain the same GLR, and similar trends to thoseshown in FIG. 2d are found, but with optimum spray characteristicsoccurring at higher obscurations. Using 125 micrometer diameter nozzlesand GLR values of 0.2, liquid flowrates of 1.2 ml/min and 1.8 ml/minexhibit optimum obscurations of 50±5% and 75±5% respectively.

FIG. 3a shows an alternative nozzle assembly design which is similar tothat shown in FIGS. 1a-1c but in which the gas nozzle 6 has arectangular profile. Such a gas nozzle profile may reduce the chance ofthe liquid jet `punching` through the gas jet leading to non atomisationor partial atomisation. By suitable design of the gas and liquid nozzlesit may be possible to increase atomisation efficiency through increasedgas vortex shedding around the liquid nozzle outlet.

FIG. 3b shows another nozzle assembly in which the gas nozzle 7 has aprofile similar to that depicted in FIGS. 1a to 1c, and the liquidnozzle 8 presents a `square edge` circular orifice. A blade 9 ispositioned partly in front of gas nozzle 7, and this helps to generateturbulence, vortex shedding and shock waves in the gas jet to aidatomisation and dispersion of liquid. Blade 9 may additionally be madeto vibrate to enhance its effect.

FIG. 3c shows a further nozzle assembly in which the gas nozzleincorporates side wall extensions 10 and the liquid nozzle has a cutaway section 11 to enhance the spray shape and liquid-gas mixing.

FIG. 4 shows the average drop size produced by an atomiser using two 125micrometer diameter nozzles with a bevelled liquid outlet orifice. Twomethods of defining mean drop diameter are used; Dv,0.5 is the volumemedian diameter and D32 is the Sauter mean diameter. Measurements weremade using a Malvern ST2600 laser diffraction instrument at a position100 mm downstream from the liquid nozzle. The results show that for aconstant atomising air flow rate the drop size increases as the liquidflow rate is increased. However, the full drop size distributions forliquid flow rates of 1.0 ml/min and 1.2 ml/min show that 21.3% by massof droplets produced are smaller than 6.3 micrometers diameter, and thisis sufficient to render satisfactory operating conditions for an MDI.

FIG. 5 shows the mean drop velocity at axial distances from the liquidnozzle along the centre line of a spray produced by an atomiser usingtwo 125 micrometer diameter nozzles at 40° with a gas flowrate of 180ml/min. Measurements were made using a Dantec phase doppler anemometer.The drop velocities exhibited are less than those delivered byconventional propellant based MDIs. Such reduced drop velocity leads tolower deposition in the oropharnygeal region when sprayed into the mouthfor delivery of drug to the respiratory tract. Such characteristics mayprovide a distinct advantage over conventional propellant based MDIdelivery by leading to a reduction in local effects and systemicexposure due to oral absorption.

It will be appreciated that an atomising device may comprise a pluralityof atomising nozzle assemblies as described arranged in an array.

I claim:
 1. An atomising nozzle assembly comprising at least one nozzlehaving an outlet orifice for ejecting a liquid medicament to be atomisedand at least one nozzle having an outlet orifice for producing a jet ofgas, the at least one liquid nozzle and the at least one gas nozzlebeing configured such that the liquid medicament is impacted upon by thegas jet so as to produce a respirable spray of droplets of a sizesuitable for medical inhalation therapy, wherein the liquid is deliveredunder pressure to provide a gas to liquid mass flow rate ratio of lessthan 0.5.
 2. An atomising nozzle assembly according to claim 1,characterised in that the gas to liquid mass ratio is 0.2 or less.
 3. Anatomising nozzle assembly according to claim 1, characterised in thatthe gas nozzle and the liquid nozzle are configured such that the jet ofgas impinges on the liquid at an acute angle to atomise the liquid. 4.An atomising nozzle according to claim 1, characterised in that the gasnozzle is at least partially obscured by the liquid nozzle such that theliquid is delivered from the liquid nozzle directly into the jet of gas.5. An atomising nozzle assembly according to claim 1, characterised inthat the liquid nozzle is bevelled such that the plane of the outletorifice is approximately parallel to the plane of the outlet orifice ofthe gas nozzle.
 6. An atomising nozzle assembly according to claim 1,characterised in that the liquid and gas nozzles have an outlet diameterbetween 50 micrometers and 200 micrometers.
 7. An atomising nozzleassembly according to claim 1, characterised in that the gas nozzle andliquid nozzle are configured such that the jet of gas impinges on theliquid at an angle of between 40° and 60°.
 8. An atomising nozzleassembly according to claim 1, characterised in that the liquid nozzleoutlet is positioned up to 10 gas nozzle outlet diameters downstream ofthe gas nozzle outlet.
 9. An atomising nozzle assembly according toclaim 8, characterised in that the liquid nozzle outlet is positionedbetween 1 and 4 gas nozzle outlet diameters downstream of the gas nozzleoutlet.
 10. An atomising nozzle comprising a plurality of atomisingnozzle assemblies according to claim 1 arranged in any array.
 11. Amethod for creating a respirable spray of droplets of a size suitablefor medical inhalation therapy from a liquid medicament by introducingthe liquid medicament under pressure into a jet of gas such that theliquid is impacted upon by the said jet of gas, the gas to liquid massflowrate ratio being less than 0.5.
 12. A method according to claim 11,characterised in that the gas to liquid mass flowrate ratio is 0.2 orless.
 13. A method according to claim 11, characterised in that the jetof gas impinges on the liquid at an acute angle to the direction of flowof the liquid.
 14. A method according to claim 11, characterised in thatthe liquid is introduced into the jet of gas by means of a nozzle whichis at least partially positioned within the jet of gas.
 15. A methodaccording to claim 11, characterised in that the liquid is introducedinto the jet of gas by means of a nozzle having an outlet diameterbetween 50 micrometers and 200 micrometers.
 16. A method according toclaim 13, characterised in that the gas impinges on the liquid at anangle of between 40° and 60°.